阿霉素隐形脂质体用于肿瘤小剂量化疗的研究
|
摘要
肿瘤化疗药物不仅能够杀死肿瘤细胞,对肿瘤新生血管的内皮细胞也能发挥强大的破坏作用。阿霉素隐形脂质体用于肿瘤小剂量化疗的根本目的是抑制肿瘤血管新生,进而发挥抗癌作用。小剂量化疗(Metronomic Chemotherapy,Low Dose Chemotherapy,LDC)是一种新型的化疗方案,与传统的化疗方案相比有很大差别。传统的肿瘤化疗方案一般是采用最大耐受剂量间隔较长时间(如2-3周)给药,以确保人体正常组织在给药间隔期间得以适当的修复。但是,这种较长的给药间隔,使肿瘤血管也得以修复,结果肿瘤营养供给得以恢复,肿瘤继续生长,是传统肿瘤化疗失败的原因之一。与之相反,小剂量化疗是采用很小的剂量,频繁多剂量给药,其目的是延长化疗药物和肿瘤血管的作用时间,抑制肿瘤血管内皮细胞的生长,阻断肿瘤的营养供给,以达到“饿死”肿瘤的目的。因此,肿瘤小剂量化疗也是一种肿瘤的抗血管新生疗法。我们前期研究表明阿霉素隐形脂质体(Doxorubicin Stealth Liposomes, DSL)能够显著延长阿霉素在血液中的循环时间,并能显著促进阿霉素向肿瘤组织中的分布。因此,推测阿霉素隐形脂质体有可能比较适用于肿瘤的小剂量化疗。
本文的目的是制备阿霉素隐形脂质体,用于肿瘤的小剂量化疗,评价其急性毒性和抗肿瘤作用。实验方法:采用聚乙二醇-二硬脂酰基磷脂酰乙醇胺(PEG-DSPE),油酸、维生素E和胆固醇,阿霉素制备阿霉素隐形脂质体。利用激光粒度/Zeta电位分析仪,测定阿霉素隐形脂质体的粒度和Zeta电位。采用凝胶柱色谱法测定阿霉素隐形脂质体的载药率。通过测定给药后不同时间的血药浓度,评价阿霉素隐形脂质体的长效循环作用效果。采用昆明种小鼠,比较阿霉素隐形脂质体与阿霉素(Doxorubicin,DXR)的急性毒性。采用S180动物肿瘤模型,按小剂量化疗方案给药,评价阿霉素隐形脂体的抗肿瘤作用。结果:阿霉素隐形脂质体粒径均值为116.7±0.8 nm,Zeta电位的均值为-29.9±1.5mv,载药率达98.5±0.5 %。隐形脂质体显著提高了阿霉素的血液循环时间(p< 0.01),同时降低了阿霉素的急性毒性。采用小剂量化疗方案,阿霉素隐形脂质体与阿霉素的抗肿瘤作用均高于相应的大剂量给药的药效,而且阿霉素隐形脂质体的疗效显高于阿霉素的作用(p < 0.01)。结论:与阿霉素相比,阿霉素隐形脂质体不良反应较小,而且更适用于肿瘤的小剂量化疗。
Tumor chemotherapy drugs can kill tumor cells and play a powerful role in the destruction of the growing endothelial cells of tumor blood vessels. The purpose of this work was to prepare Adriamycin stealth liposomes for tumor low-dose chemotherapy. Low-dose chemotherapy (Metronomic Chemotherapy) is a new type of chemotherapy. Compared to traditional chemotherapy, it has many characteristics. Traditional tumor chemotherapy is generally known as the maximum tolerated dose therapy using a longer time interval (eg 2-3 weeks) administration to ensure that human normal tissues in the interval between administrations could recover. However, the longer delivery intervals make it possible for tumor blood vessel formation to result in tumor nutrition supply recovered and make the tumor continue to grow. This is one of the reasons for the failure of the traditional tumor chemotherapy. In contrast, low-dose chemo- therapy is the use of very small doses, such as one-tenth of the traditional dose and shortens the delivery time interval, that is, more frequent dosing. Low-dose chemotherapy fundamental purpose is to extend the chemotherapy drugs circulation time in the blood and inhibit the tumor vascular endothelial cell growth by blocking the tumor's nutrient supply, and achieve the "starving to death" of cancer tissue. Therefore, low-dose chemotherapy is also known as a type of anti-tumor angiogenesis therapy. However, there is no specific principle how to choose the appropriate drug for tumor low-dose chemotherapy. We have reported that Adriamycin stealth liposomes (Doxorubicin Stealth Liposomes) can significantly extend the doxorubicin circulation time in the blood, and could significantly promote doxorubicin to be distributed into tumor tissue. Therefore, we predict doxorubicin stealth liposomes have may be more applicable to low-dose cancer chemotherapy.
The purpose of this paper is to prepare doxorubicin stealth liposomes for tumor of low-dose chemotherapy and evaluate its acute toxicity and anti-tumor effects. PEG-DSPE) oleic acid, vitamin E and cholesterol were used to prepare stealth liposomes. Lipid bilayer mosaic has acid molecules. When the pH was increased to 7.4, some oleic acid molecules could be changed into positively charged ones and attracts doxorubicin molecules into the liposomes. Laser Particle Size / Zeta potential analyzer was used to characterize Doxorubicin Stealth Liposomes. The loading efficiency for Doxorubicin was determined using the Sephadex G50 column chromatography method. The acute toxicity of Doxorubicin Stealth Liposomes was evaluated using mice. The long time blood circulation role of Doxorubicin Stealth Liposomes was evaluated by measuring blood drug concentration at different times after administration. The anti-tumor effect of Doxorubicin Stealth Liposomes was studied in S180 animal tumor model by small-dose chemotherapy administration. The results: Doxorubicin Stealth Liposomes mean diameter 116.7±0.8 nm, Zeta potential of the average -29.9±1.5 mv, drug-loading rate of 98.5±0.5%. Doxorubicin Stealth liposomes Doxorubicin significantly prolonged the blood circulation time (p <0.01), while reducing the acute toxicity of Doxorubicin. Following low-dose chemotherapy, both Doxorubicin Stealth Liposomes and Doxorubicin have stronger anti-tumor effects than the corresponding high-dose chemotherapy, but the anti-cancer effect of Doxorubicin Stealth Liposomes was much greater than that of Doxorubicin in low dose chemotherapy(p <0.01). Conclusion: Compared with Doxorubicin, Doxorubicin Stealth Liposomes has fewer adverse effects, but much more antitumor action, which indicates Doxorubicin Stealth Liposome, is applicable to tumor low-dose chemotherapy.
本文的目的是制备阿霉素隐形脂质体,用于肿瘤的小剂量化疗,评价其急性毒性和抗肿瘤作用。实验方法:采用聚乙二醇-二硬脂酰基磷脂酰乙醇胺(PEG-DSPE),油酸、维生素E和胆固醇,阿霉素制备阿霉素隐形脂质体。利用激光粒度/Zeta电位分析仪,测定阿霉素隐形脂质体的粒度和Zeta电位。采用凝胶柱色谱法测定阿霉素隐形脂质体的载药率。通过测定给药后不同时间的血药浓度,评价阿霉素隐形脂质体的长效循环作用效果。采用昆明种小鼠,比较阿霉素隐形脂质体与阿霉素(Doxorubicin,DXR)的急性毒性。采用S180动物肿瘤模型,按小剂量化疗方案给药,评价阿霉素隐形脂体的抗肿瘤作用。结果:阿霉素隐形脂质体粒径均值为116.7±0.8 nm,Zeta电位的均值为-29.9±1.5mv,载药率达98.5±0.5 %。隐形脂质体显著提高了阿霉素的血液循环时间(p< 0.01),同时降低了阿霉素的急性毒性。采用小剂量化疗方案,阿霉素隐形脂质体与阿霉素的抗肿瘤作用均高于相应的大剂量给药的药效,而且阿霉素隐形脂质体的疗效显高于阿霉素的作用(p < 0.01)。结论:与阿霉素相比,阿霉素隐形脂质体不良反应较小,而且更适用于肿瘤的小剂量化疗。
Tumor chemotherapy drugs can kill tumor cells and play a powerful role in the destruction of the growing endothelial cells of tumor blood vessels. The purpose of this work was to prepare Adriamycin stealth liposomes for tumor low-dose chemotherapy. Low-dose chemotherapy (Metronomic Chemotherapy) is a new type of chemotherapy. Compared to traditional chemotherapy, it has many characteristics. Traditional tumor chemotherapy is generally known as the maximum tolerated dose therapy using a longer time interval (eg 2-3 weeks) administration to ensure that human normal tissues in the interval between administrations could recover. However, the longer delivery intervals make it possible for tumor blood vessel formation to result in tumor nutrition supply recovered and make the tumor continue to grow. This is one of the reasons for the failure of the traditional tumor chemotherapy. In contrast, low-dose chemo- therapy is the use of very small doses, such as one-tenth of the traditional dose and shortens the delivery time interval, that is, more frequent dosing. Low-dose chemotherapy fundamental purpose is to extend the chemotherapy drugs circulation time in the blood and inhibit the tumor vascular endothelial cell growth by blocking the tumor's nutrient supply, and achieve the "starving to death" of cancer tissue. Therefore, low-dose chemotherapy is also known as a type of anti-tumor angiogenesis therapy. However, there is no specific principle how to choose the appropriate drug for tumor low-dose chemotherapy. We have reported that Adriamycin stealth liposomes (Doxorubicin Stealth Liposomes) can significantly extend the doxorubicin circulation time in the blood, and could significantly promote doxorubicin to be distributed into tumor tissue. Therefore, we predict doxorubicin stealth liposomes have may be more applicable to low-dose cancer chemotherapy.
The purpose of this paper is to prepare doxorubicin stealth liposomes for tumor of low-dose chemotherapy and evaluate its acute toxicity and anti-tumor effects. PEG-DSPE) oleic acid, vitamin E and cholesterol were used to prepare stealth liposomes. Lipid bilayer mosaic has acid molecules. When the pH was increased to 7.4, some oleic acid molecules could be changed into positively charged ones and attracts doxorubicin molecules into the liposomes. Laser Particle Size / Zeta potential analyzer was used to characterize Doxorubicin Stealth Liposomes. The loading efficiency for Doxorubicin was determined using the Sephadex G50 column chromatography method. The acute toxicity of Doxorubicin Stealth Liposomes was evaluated using mice. The long time blood circulation role of Doxorubicin Stealth Liposomes was evaluated by measuring blood drug concentration at different times after administration. The anti-tumor effect of Doxorubicin Stealth Liposomes was studied in S180 animal tumor model by small-dose chemotherapy administration. The results: Doxorubicin Stealth Liposomes mean diameter 116.7±0.8 nm, Zeta potential of the average -29.9±1.5 mv, drug-loading rate of 98.5±0.5%. Doxorubicin Stealth liposomes Doxorubicin significantly prolonged the blood circulation time (p <0.01), while reducing the acute toxicity of Doxorubicin. Following low-dose chemotherapy, both Doxorubicin Stealth Liposomes and Doxorubicin have stronger anti-tumor effects than the corresponding high-dose chemotherapy, but the anti-cancer effect of Doxorubicin Stealth Liposomes was much greater than that of Doxorubicin in low dose chemotherapy(p <0.01). Conclusion: Compared with Doxorubicin, Doxorubicin Stealth Liposomes has fewer adverse effects, but much more antitumor action, which indicates Doxorubicin Stealth Liposome, is applicable to tumor low-dose chemotherapy.
引文
[1]Gerhardt H ,Golding M ,Fruttiger M , et al . VEGF guides angiogenic sprouting utilizing endot helial tip cell filopodia . J Cell Biol , 2003 , 161 (6) : 1163-1177.
[2]Djonov V , Baum O , Burri P H. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res , 2003 , 314(1) : 107-117.
[3]Burri P H , Djonov V. Intussusceptive angiogenesis - the alternative to capillary sprouting. Mol Aspects Med ,2002 ,23 (6S) : S12S27.
[4]Holash J ,Maisonpierre P C ,Compton D , et al . Vessel cooption , regression , and growth in tumors mediated by angiopoietins and VEGF. Science , 1999 , 284 (5422) : 1994-1998.
[5]Asahara T ,Murohara T ,Sullivan A , et al . Isolation of putative progenitor endot helial cells for angiogenesis.Science ,1997, 75 (5302) : 964-967.
[6]Goon P K Y,Lip G Y H ,Boos C J , et al . Circulating endothelial cells , endot helial progenitor cells ,and endot helial microparticles in cancer. Neoplasia , 2006 , 8 (2) : 79-88.
[7]Heissig B ,Hattori K,Dias S , et al . Recruitment of stem and progenitor cells from t he bone marrow niche requires MMP29 mediated release of Kit ligand . Cell,2002 , 109 (5) : 625-637.
[8]Chang Y S ,di Tomaso E ,McDonald DM , et al . Mosaic blood vessels in tumors : f requency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A ,2000 , 97 (26) :14608-14613.
[9]Di Tomaso E ,Capen D , Haskell A , et al . Mosaic tumor vessels : cellular basis and ultra structure of focal regions lacking endothelial cell markers. Cancer Res , 2005 , 65 ( 13 ) :5740-5749.
[10]Maniotis AJ , Folberg R , Hess A , et al . Vascular channel formation by human melanoma cells in vi vo and in vit ro : vasculogenic mimicry. Am J Pat hol ,1999 , 155 (3) : 739-752.
[11]Hendrix M J , Seftor EA , Hess AR , et al . Vasculogenic mimicry and tumor2cell plasticity : lessons f rom melanoma. Nat Rev Cancer, 2003 , 3 (6) : 4112421.
[12]Quesada A R ,Munoz2Chapuli R , Medina M A. Antiangiogenic drugs : from bench to clinical t rials. Med Res Rev,2006 , 26 (4) : 483-530.
[13]Motzer R J ,Michaelson M D ,Redman B G, et al . Activity of SU11248 , a multitargeted inhibitor of vascular endot helial growt h factor receptor and platelet2derived growt h factor receptor , in patient s wit h metastatic renal cell carcinoma. J Clin Oncol,2006,24 (1) : 16-24.
[14]Faivre S ,Delbaldo C ,Vera K, et al . Safety , pharmacokinetic, and antitumor activity of SU11248 , a novel oral multitarget tyrosine kinase inhibitor, in patient s wit h cancer. J Clin Oncol,2006,24 (1) : 25-35.
[15]Schiller, J. H. et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl.J. Med. 2002,346:92-98.
[16]Leaf, C. Why we’re losing the war on cancer (and how tow in it). Fortune 2004,149:77–97.
[17]Nieto, Y. The verdict is not in yet. Analysis of the randomized Continuous low-dose anti-angiogenic (metronomic) chemotherapy: from the research laboratory into the oncology clinic. Ann. Oncol. 2002,13, 12–15.
[18]Hahnfeldt, P., Folkman, J. & Hlatky, L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J. Theor. Biol. 2003,220,545-554.
[19]Stoll, B. R., Migliorini, C., Kadambi, A., Munn, L. L. & Jain, R. K. A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for anti-angiogenic therapy. Blood 2003,102, 2555-2561.
[20]Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drugresistant cancer. Cancer Res. 2000,60, 1878-1886.
[21]Miller,K. D.,Sweeney,C. J. & Sledge,G. W. Redefining the target: chemotherapeutics as antiangiogenics. J. Clin. Oncol. 2001,19, 1195-1206.
[22]Man, S. et al. Antitumor and anti-angiogenic effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res.2002, 62:2731-2735.
[23]Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004, 4(6) : 423-36.
[24]李长毅,张明川,梅同华.持续小剂量化疗对A549肺癌PTEN基因和凋亡的影响.第三军医大学学报-2007, 29(18) : 1760-1763.
[25]Gabizon A., Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.. Proc. Natl. Acad. Sci. USA, 1988,85: 6949-6953.
[26]Gabizon A., Papahadjopoulos D. The role of surface charge and hydrophilic groups on liposome clearance in vivo. Biochim. Biophys. Acta, 1992, 1103: 94-100.
[27]Allen T. M., Hansen C., Martin F., Redemann C., Yau-Young A. Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo.. Biochim. Biophys. Acta, 1991,1066: 29-36.
[28]Klibanov A. L., Maruyama K., Torchilin V. P., Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes.. FEBS Lett., 1990,268: 235-237.
[29]Senior J., Delgado C., Fisher D., Tilcock C., Gregoriadis G. Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: studies with poly(ethylene glycol)-coated vesicles.. Biochim. Biophys. Acta, 1991,1062: 77-82.
[30]Blume G., Cevc G. Liposomes for the sustained drug release in vivo.. Biochim. Biophys. Acta, 1990,1029: 91-97.
[34]Woodle M. C., Lasic D. D. Sterically stabilized liposomes.. Biochim.Biophys. Acta, 1992,1113: 171-199.
[35]Lasic D. D., Martin F. J., Gabizon A., Huang S. K., Papahadjopoulos D. Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times.. Biochim. Biophys. Acta, 1991,1070: 187-192.
[36]Oku N., Namba Y., Okada S. Tumor accumulation of novel RES- avoiding liposomes.. Biochim. Biophys. Acta, 1992,1126: 255-260.
[37]Peterson, H. I. (ed.). Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors. Boca Raton, FL: CRC Press,1979.
[38]Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.. J. Clin. Investig., 1989,84: 1470-1478.
[39]Maeda H. SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv. Drug Delivery Rev., 1991,6: 181-202.
[40]Duncan R. Drug-polymer conjugates: potential for improved chemo- therapy. Anticancer Drugs, 1992,3: 175-210.
[41]Huang S. K., Lee K-D., Hong K., Friend D. S., Papahadjopoulos D. Microscopic localization of sterically stabilized liposomes in colon carcinoma- bearing mice.. Cancer Res., 1992,52: 5135-5143, 1992.
[42]赵梦丹,俞飞江,虞和永.阿霉素脂质体的制备及其体外细胞毒活性.浙江医学.2008, 30(4) : 337-339.
[43]于美丽,王勇,舒贵明,朱争艳,方叔晶,王黎.卵磷脂和氢化卵磷脂长循环阿霉素脂质体的制备及缓释研究.北京生物医学工程. 2006, 25(6) : 654-657.
[44]刘一,边原,叶云.阿霉素抗肿瘤作用的研究进展.泸州医学院学报. 2008, 31(1) : 101-103.
[2]Djonov V , Baum O , Burri P H. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res , 2003 , 314(1) : 107-117.
[3]Burri P H , Djonov V. Intussusceptive angiogenesis - the alternative to capillary sprouting. Mol Aspects Med ,2002 ,23 (6S) : S12S27.
[4]Holash J ,Maisonpierre P C ,Compton D , et al . Vessel cooption , regression , and growth in tumors mediated by angiopoietins and VEGF. Science , 1999 , 284 (5422) : 1994-1998.
[5]Asahara T ,Murohara T ,Sullivan A , et al . Isolation of putative progenitor endot helial cells for angiogenesis.Science ,1997, 75 (5302) : 964-967.
[6]Goon P K Y,Lip G Y H ,Boos C J , et al . Circulating endothelial cells , endot helial progenitor cells ,and endot helial microparticles in cancer. Neoplasia , 2006 , 8 (2) : 79-88.
[7]Heissig B ,Hattori K,Dias S , et al . Recruitment of stem and progenitor cells from t he bone marrow niche requires MMP29 mediated release of Kit ligand . Cell,2002 , 109 (5) : 625-637.
[8]Chang Y S ,di Tomaso E ,McDonald DM , et al . Mosaic blood vessels in tumors : f requency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A ,2000 , 97 (26) :14608-14613.
[9]Di Tomaso E ,Capen D , Haskell A , et al . Mosaic tumor vessels : cellular basis and ultra structure of focal regions lacking endothelial cell markers. Cancer Res , 2005 , 65 ( 13 ) :5740-5749.
[10]Maniotis AJ , Folberg R , Hess A , et al . Vascular channel formation by human melanoma cells in vi vo and in vit ro : vasculogenic mimicry. Am J Pat hol ,1999 , 155 (3) : 739-752.
[11]Hendrix M J , Seftor EA , Hess AR , et al . Vasculogenic mimicry and tumor2cell plasticity : lessons f rom melanoma. Nat Rev Cancer, 2003 , 3 (6) : 4112421.
[12]Quesada A R ,Munoz2Chapuli R , Medina M A. Antiangiogenic drugs : from bench to clinical t rials. Med Res Rev,2006 , 26 (4) : 483-530.
[13]Motzer R J ,Michaelson M D ,Redman B G, et al . Activity of SU11248 , a multitargeted inhibitor of vascular endot helial growt h factor receptor and platelet2derived growt h factor receptor , in patient s wit h metastatic renal cell carcinoma. J Clin Oncol,2006,24 (1) : 16-24.
[14]Faivre S ,Delbaldo C ,Vera K, et al . Safety , pharmacokinetic, and antitumor activity of SU11248 , a novel oral multitarget tyrosine kinase inhibitor, in patient s wit h cancer. J Clin Oncol,2006,24 (1) : 25-35.
[15]Schiller, J. H. et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl.J. Med. 2002,346:92-98.
[16]Leaf, C. Why we’re losing the war on cancer (and how tow in it). Fortune 2004,149:77–97.
[17]Nieto, Y. The verdict is not in yet. Analysis of the randomized Continuous low-dose anti-angiogenic (metronomic) chemotherapy: from the research laboratory into the oncology clinic. Ann. Oncol. 2002,13, 12–15.
[18]Hahnfeldt, P., Folkman, J. & Hlatky, L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J. Theor. Biol. 2003,220,545-554.
[19]Stoll, B. R., Migliorini, C., Kadambi, A., Munn, L. L. & Jain, R. K. A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for anti-angiogenic therapy. Blood 2003,102, 2555-2561.
[20]Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drugresistant cancer. Cancer Res. 2000,60, 1878-1886.
[21]Miller,K. D.,Sweeney,C. J. & Sledge,G. W. Redefining the target: chemotherapeutics as antiangiogenics. J. Clin. Oncol. 2001,19, 1195-1206.
[22]Man, S. et al. Antitumor and anti-angiogenic effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res.2002, 62:2731-2735.
[23]Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004, 4(6) : 423-36.
[24]李长毅,张明川,梅同华.持续小剂量化疗对A549肺癌PTEN基因和凋亡的影响.第三军医大学学报-2007, 29(18) : 1760-1763.
[25]Gabizon A., Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.. Proc. Natl. Acad. Sci. USA, 1988,85: 6949-6953.
[26]Gabizon A., Papahadjopoulos D. The role of surface charge and hydrophilic groups on liposome clearance in vivo. Biochim. Biophys. Acta, 1992, 1103: 94-100.
[27]Allen T. M., Hansen C., Martin F., Redemann C., Yau-Young A. Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo.. Biochim. Biophys. Acta, 1991,1066: 29-36.
[28]Klibanov A. L., Maruyama K., Torchilin V. P., Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes.. FEBS Lett., 1990,268: 235-237.
[29]Senior J., Delgado C., Fisher D., Tilcock C., Gregoriadis G. Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: studies with poly(ethylene glycol)-coated vesicles.. Biochim. Biophys. Acta, 1991,1062: 77-82.
[30]Blume G., Cevc G. Liposomes for the sustained drug release in vivo.. Biochim. Biophys. Acta, 1990,1029: 91-97.
[34]Woodle M. C., Lasic D. D. Sterically stabilized liposomes.. Biochim.Biophys. Acta, 1992,1113: 171-199.
[35]Lasic D. D., Martin F. J., Gabizon A., Huang S. K., Papahadjopoulos D. Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times.. Biochim. Biophys. Acta, 1991,1070: 187-192.
[36]Oku N., Namba Y., Okada S. Tumor accumulation of novel RES- avoiding liposomes.. Biochim. Biophys. Acta, 1992,1126: 255-260.
[37]Peterson, H. I. (ed.). Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors. Boca Raton, FL: CRC Press,1979.
[38]Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.. J. Clin. Investig., 1989,84: 1470-1478.
[39]Maeda H. SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv. Drug Delivery Rev., 1991,6: 181-202.
[40]Duncan R. Drug-polymer conjugates: potential for improved chemo- therapy. Anticancer Drugs, 1992,3: 175-210.
[41]Huang S. K., Lee K-D., Hong K., Friend D. S., Papahadjopoulos D. Microscopic localization of sterically stabilized liposomes in colon carcinoma- bearing mice.. Cancer Res., 1992,52: 5135-5143, 1992.
[42]赵梦丹,俞飞江,虞和永.阿霉素脂质体的制备及其体外细胞毒活性.浙江医学.2008, 30(4) : 337-339.
[43]于美丽,王勇,舒贵明,朱争艳,方叔晶,王黎.卵磷脂和氢化卵磷脂长循环阿霉素脂质体的制备及缓释研究.北京生物医学工程. 2006, 25(6) : 654-657.
[44]刘一,边原,叶云.阿霉素抗肿瘤作用的研究进展.泸州医学院学报. 2008, 31(1) : 101-103.